WO2013053927A1 - Diagnostic photodynamique d'anomalies du tissu épithélial sous-jacent de l'œsophage au moyen d'un ester de 5-ala - Google Patents

Diagnostic photodynamique d'anomalies du tissu épithélial sous-jacent de l'œsophage au moyen d'un ester de 5-ala Download PDF

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Publication number
WO2013053927A1
WO2013053927A1 PCT/EP2012/070346 EP2012070346W WO2013053927A1 WO 2013053927 A1 WO2013053927 A1 WO 2013053927A1 EP 2012070346 W EP2012070346 W EP 2012070346W WO 2013053927 A1 WO2013053927 A1 WO 2013053927A1
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pharmaceutically acceptable
ala ester
esophagus
ala
acceptable salt
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PCT/EP2012/070346
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English (en)
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Ketil WIDERERG
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Photocure Asa
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Priority to US14/351,770 priority Critical patent/US20140276107A1/en
Priority to EP12770170.4A priority patent/EP2766049A1/fr
Publication of WO2013053927A1 publication Critical patent/WO2013053927A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0036—Porphyrins

Definitions

  • This invention relates generally to the diagnosis of abnormalities of the epithelial- lined surface of the esophagus. More particularly, it relates to the use of esters of 5-aminolevulinic acid (5-ALA) in methods of photodynamic diagnosis of Barrett's esophagus and in diagnostic methods for monitoring the progression of the disease.
  • esters of 5-aminolevulinic acid (5-ALA) in methods of photodynamic diagnosis of Barrett's esophagus and in diagnostic methods for monitoring the progression of the disease.
  • Esophageal cancer includes both squamous cell carcinoma and adenocarcinoma.
  • the incidence of esophageal adenocarcinoma has increased by almost 400% during recent decades and it is now the cancer with the fastest rising incidence in the Western world. Although it can be treated, for example by surgery or chemotherapy, it is rare that the disease can be cured; the mortality rate for those diagnosed with the disease is over 85%. Early diagnosis is therefore critical in order to improve survival rates.
  • Barrett's esophagus is a condition in which the normal squamous lining of the distal esophagus is replaced by columnar epithelium with intestinal metaplasia. It may be recognised endoscopically by a salmon- coloured mucosa above the lower esophageal sphincter that separates the stomach from the esophagus (a normal esophagus is usually light pink in colour).
  • GSD gastro-esophageal reflux disorder
  • Intestinal metaplasia is a pre-malignant condition that, through a series of cellular changes, may develop further into low-grade dysplasia, high-grade dysplasia and, ultimately, adenocarcinoma of the esophagus.
  • Dysplasia is not usually visible when using standard endoscopic surveillance methods and can remain undetected until the invasive adenocarcinoma stage.
  • the ability to monitor the various stages of the disease is further complicated by the simultaneous presence of metaplasia as well as dysplasia and early cancer which are difficult to differentiate with standard endoscopy techniques.
  • the ability not only to diagnose Barrett's esophagus at an early stage, but also to monitor its progression is key to preventing esophageal cancer and to improving survival rates.
  • metabolically active tissue such as dysplastic or cancerous tissue
  • metabolically active tissue such as dysplastic or cancerous tissue
  • the mechanisms are still not fully understood, but studies suggest that accumulation is not due to selective uptake of 5-ALA by pre-cancerous or cancerous cells. Rather, there are similar levels of uptake in all cell types, but the processes of conversion and elimination are different in metabolically active cells, leading to a concentration gradient between abnormally proliferating cells and normal tissue.
  • intraepithelial neoplasia and adenocarcinoma it is not accurate in detecting low- grade neoplastic tissue, which is likely to develop into cancerous tissue.
  • WO 2009/109569 suggests the use of esters of 5-ALA, specifically 5-ALA hexyl ester, for detecting early stage dysplasia in the esophagus and esophageal cancer.
  • later-stage abnormalities e.g. precancerous
  • 5-ALA esters are already known to have a number of advantages over 5-ALA itself, such as faster penetration into tissues; better enhancement of PplX production; improved selectivity for the target tissue, etc.
  • the use of 5-ALA esters provides an enhanced fluorescence contrast between dysplastic, neoplastic and cancer tissue and metaplastic / normal tissue.
  • the reduction in background noise from both normal and metaplastic tissues when using the 5-ALA esters provides for superior demarcation of dysplastic, neoplastic and cancer tissues.
  • the invention provides a method of photodynamic diagnosis of an abnormality of the epithelial lining of the esophagus, said method comprising the following steps: (a) administering to a subject, e.g. a human or non-human animal, a 5-ALA ester, or a pharmaceutically acceptable salt thereof;
  • differences in fluorescence intensity from the different tissue types i.e. both normal and abnormal, e.g. normal, metaplastic, dysplastic, neoplastic and cancerous
  • differences in fluorescence intensity may be used to indicate the presence or absence of any abnormality within the target area.
  • the invention provides a 5-ALA ester, or a pharmaceutically acceptable salt thereof, for use in a method of photodynamic diagnosis as herein described.
  • diagnosis encompasses not only the detection (i.e. identification) of an abnormality, but also monitoring or surveillance of its progression and development.
  • Abnormalities of the epithelial lining of the esophagus encompass not only cancerous conditions but also conditions which may be considered pre-cancerous or non-cancerous.
  • pre-cancerous condition denotes a tissue abnormality which, if left untreated, may ultimately lead to cancer. It is a generalized state associated with a significantly increased risk of cancer. A pre-cancerous condition may manifest itself by extensive and/or abnormal proliferation of cells, e.g. dysplasia and/or neoplasia. Cancerous conditions in the esophagus include basal cell carcinomas and adenocarcinomas.
  • non-cancerous conditions includes tissue abnormalities with no or low malignant potential such as metaplasia.
  • the invention relates to the diagnosis of Barrett's esophagus.
  • Barrett's esophagus is intended to encompass the presence of metaplastic epithelium. In later stage Barrett's esophagus, the presence of dysplastic tissue may be observed.
  • Metaplastic denotes cells or tissues which have been reversibly replaced by another differentiated cell type. Metaplastic tissue is considered non- carcinogenic.
  • displastic denotes the abnormal development or growth of cells or tissues.
  • neoplastic denotes the abnormal proliferation of cells or tissues. Both the presence of dysplastic and neoplastic tissues is considered a pre-cancerous condition.
  • 5-ALA ester denotes esters of 5-aminolevulinic acid (i.e. 5-amino-4-oxo- pentanoic acid).
  • pharmaceutically acceptable salt denotes a salt that is suitable for use in a pharmaceutical product and which fulfils the requirements related to for instance safety, bioavailability and tolerability (see for instance P. H. Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002).
  • the invention encompasses the photodynamic diagnosis of early stage Barrett's esophagus, i.e. detection of the presence of metaplastic cells, using the 5-ALA esters herein described. Once metaplasia has been detected, these 5-ALA esters may also be used in photodynamic methods for monitoring the progression of the disease, for example in detecting early and/or late stage dysplasia.
  • Monitoring of patients with Barrett's esophagus at regular intervals, e.g. annually or bi-annually enables early detection of any progression of the disease to pre-cancerous (e.g. dysplastic and/or neoplastic) and/or cancerous (e.g. adenocarcinoma) stages.
  • Detection of fluorescence may be used to identify the presence of certain abnormal cell or tissue types, for example, any of metaplastic, dysplastic or neoplastic cells or tissues.
  • measurement of fluorescence intensity from the esophagus may be used to distinguish between the different types of cells or tissues which may be present. Identification of any high-risk areas (e.g. those comprising dysplastic or neoplastic cells) for operative intervention forms a preferred aspect of the invention.
  • results from any of the diagnostic methods which are described herein may also provide a useful guide for any subsequent biopsy and/or as a guide to the areas for subsequent treatment.
  • the methods of diagnosis may therefore be performed prior to carrying out a biopsy and/or therapeutic treatment.
  • 5-ALA esters both in methods of photodynamic therapy (PDT) and photodynamic diagnosis (PDD) is well known in the scientific and patent literature (see, for example, WO 2006/051269, WO 2005/092838, WO 03/01 1265,
  • the 5-ALA esters useful in accordance with the invention may be any ester of 5-ALA capable of forming protoporphyrins, e.g. PplX or a PplX derivative (e.g. a PplX ester) in vivo.
  • PplX an ester of 5-ALA capable of forming protoporphyrins
  • PplX derivative e.g. a PplX ester
  • esters will be a precursor of PplX or of a PplX derivative in the biosynthetic pathway for haem and which are therefore capable of inducing an accumulation of PplX following administration in vivo.
  • Esters of 5-ALA which are N-substituted may be used in the invention.
  • those compounds in which the 5-amino group is unsubstituted are particularly preferred.
  • Such compounds are generally known and described in the literature; see, for example, WO 96/28412 and WO 02/10120 to Photocure ASA, the contents of which are incorporated herein by reference.
  • Esters resulting from a reaction of 5-ALA with substituted or unsubstituted alkanols i.e. alkyi esters and substituted alkyi esters, and pharmaceutically acceptable salts thereof, are especially preferred for use in the invention.
  • Examples of such compounds include those of general formula I and pharmaceutically acceptable salts thereof: R 2 2N-CH 2 COCH2-CH 2 CO-OR 1 (I) wherein
  • R 1 represents an optionally substituted alkyi group
  • R 2 each independently represents a hydrogen atom or a group R 1 .
  • alkyi includes any long or short chain, cyclic, straight-chained or branched, saturated or unsaturated aliphatic hydrocarbon group.
  • Unsaturated alkyi groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Unless stated otherwise, such alkyi groups may contain up to 40 carbon atoms. However, alkyi groups containing up to 30 carbon atoms, preferably up to 10, particularly preferably up to 8, especially preferably up to 6 carbon atoms, are preferred.
  • the R 1 groups are substituted or unsubstituted alkyi groups. If R 1 is a substituted alkyi group, one or more substituents are either attached to the alkyi group and/or interrupt the alkyi group. Suitable substituents that are attached to the alkyi group are those selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, -SR 3 , -NR 3 2 and -PR 3 2 , wherein R 3 is a hydrogen atom or a Ci -6 alkyi group. Suitable substituents that interrupt the alkyi group are those selected from -0-, -NR 3 -, -S- or -PR 3 (where R 3 is as hereinbefore defined).
  • R 1 may be an alkyi group substituted with one or more aryl substituents, i.e. aryl groups, preferably an alkyi group substituted with one aryl group.
  • aryl group denotes an aromatic group which may or may not contain heteroatoms like nitrogen, oxygen or sulfur.
  • Aryl groups which do not contain heteroatoms are preferred.
  • Preferred aryl groups comprise up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example, 10 or 6 carbon atoms.
  • Preferred embodiments of aryl groups are phenyl and naphthyl, especially phenyl.
  • the aryl group may optionally be substituted by one or more, more preferably one or two, substituents.
  • the aryl group is substituted at the meta- or para- position, most preferably the para- position.
  • Suitable substituents include haloalkyi (e.g. trifluoromethyl), alkoxy (preferably alkoxy groups containing 1 to 6 carbon atoms), halo (e.g. iodo, bromo, chloro or fluoro, preferably chloro or fluoro), nitro and Ci -6 alkyl (preferably C1-4 alkyl).
  • Preferred Ci -6 alkyl groups include methyl, isopropyl and t-butyl, particularly methyl.
  • Particularly preferred aryl substituents are chloro and nitro. However, still more preferably the aryl group is unsubstituted.
  • aryl-substituted R 1 groups include benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-[t-butyl]benzyl,
  • R 1 groups 4- diphenyl-methyl and benzyl-5-[(1 -acetyloxyethoxy)-carbonyl]. More preferred such R 1 groups are benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 4-nitrobenzyl and 4-chlorobenzyl. Most preferred is benzyl.
  • R 1 is a substituted alkyl group, one or more oxo substituents are preferred.
  • such groups are straight-chained C4-12 alkyl groups which are substituted by one or more oxo groups, preferably by one to five oxo groups.
  • the oxo groups are preferably present in the substituted alkyl group in an alternating order, i.e. resulting in short chain polyethylene glycol substituents.
  • Preferred examples of such groups include 3,6-dioxa-1-octyl and 3,6,9-trioxa-1 -decyl.
  • R 1 is an alkyl group interrupted by one or more oxygen atoms (ether or polyether group), preferably a straight-chained C 4-12 alkyl and more preferably a straight-chained C 6- io alkyl group being interrupted by 1 to 4 oxygen atoms, more preferably a straight-chained polyethylene glycol group (-(CH 2 )2-0-) n with n being an integer of from 1 to 5.
  • oxygen atoms ether or polyether group
  • R 1 is an unsubstituted alkyl group
  • R 1 groups that are saturated straight-chained or branched alkyl groups are preferred.
  • R 1 is a saturated straight-chained alkyl group
  • Ci-io straight-chained alkyl groups are preferred.
  • suitable straight-chained alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl.
  • Particularly preferred are Ci -6 straight-chained alkyl groups. Most particularly preferred is n-hexyl.
  • R 1 is a saturated branched alkyl group
  • such branched alkyl groups preferably consist of a stem of 4 to 8, preferably 5 to 8 straight-chained carbon atoms and said stem is branched by one or more Ci-6 alkyl groups, preferably Ci -2 alkyl groups.
  • Examples of such saturated branched alkyl groups include 2-methylpentyl, 4-methylpentyl, 1 -ethylbutyl and
  • each R 2 independently represents a hydrogen atom or a group R 1 . Particularly preferred for use in the invention are those compounds of formula I in which at least one R 2 represents a hydrogen atom. In especially preferred compounds each R 2 represents a hydrogen atom.
  • Preferred 5-ALA esters for use in the invention include methyl ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester, pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methoxyethyl ALA ester, 2-methylpentyl ALA ester, 4-methylpentyl ALA ester, 1-ethylbutyl ALA ester, 3,3 -dimethyl-1 -butyl ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester,
  • the 5-ALA esters for use in the invention may be in the form of a free amine, e.g. -NH 2 , -NHR 2 or -NR 2 R 2 or preferably in the form of a pharmaceutically acceptable salt.
  • Such salts preferably are acid addition salts with pharmaceutically acceptable organic or inorganic acids.
  • Suitable acids include, for example, hydrochloric, nitric, hydrobromic, phosphoric, sulfuric, sulfonic and sulfonic acid derivatives (the salts of ALA-esters and the latter acids are described in WO 2005/092838 to Photocure ASA, the entire contents of which are incorporated herein by reference).
  • a preferred acid is hydrochloride acid, HCI.
  • nitric acid sulfonic acid and sulfonic acid derivatives (e.g. mesylate or tosylate).
  • Procedures for salt formation are conventional in the art and are for instance described in WO 2005/092838.
  • Preferred compounds of formula I and pharmaceutically acceptable salts thereof for use in the invention are those wherein R 1 represents an unsubstituted alkyl group, preferably an unsubstituted , saturated, straight-chained or branched, alkyl group (e.g. a C 1-10 alkyl group). Particularly preferred compounds are those wherein R 1 is hexyl, more preferably n-hexyl, and both R 2 represent hydrogen, i.e. 5-ALA hexyl ester and pharmaceutically acceptable salts thereof.
  • the preferred compound for use in the invention is 5-ALA hexyl ester and its pharmaceutically acceptable salts, preferably the hydrochloride salt, nitrate salt or sulfonic acid salts or sulfonic acid derivative salts, such as mesylate, tosylate or napsylate.
  • 5-ALA esters and pharmaceutically acceptable salts thereof for use in the invention may be prepared by any conventional procedure available in the art, e.g. as described in WO 96/28412, WO 02/10120, WO 03/041673 and in N. Fotinos et al., Photochemistry and Photobiology 2006: 82: 994-1015 and the cited literature references therein. Briefly, 5-ALA esters may be prepared by reaction of 5-ALA with the appropriate alcohol in the presence of a catalyst, e.g. an acid.
  • a catalyst e.g. an acid
  • 5-ALA esters may be prepared as described hereinbefore by reaction of a pharmaceutically acceptable 5-ALA salt, e.g. 5-ALA hydrochloride with the appropriate alcohol.
  • a pharmaceutically acceptable 5-ALA salt e.g. 5-ALA hydrochloride
  • compounds for use in the invention like 5-ALA hexyl ester may be available commercially, e.g. from
  • the compounds for use according to the invention may be formulated in any conventional manner with one or more physiologically acceptable carriers or excipients, according to techniques well known in the art. Where appropriate, the compounds or compositions according to the invention are sterilized, e.g. by ⁇ -irradiation, autoclaving or heat sterilization, before or after the addition of a carrier or excipient where that is present, to provide sterile formulations.
  • compositions for use in the invention may be administered systemically (e.g. orally or parenterally), but preferably these will be administered locally.
  • Localization e.g. orally or parenterally
  • administration may be achieved by injection or, more preferably, by topical application (e.g. by local instillation) at or near the desired target site.
  • Administration may also be carried out distally at the upper end of the esophagus, e.g. by oral administration.
  • oral administration of certain formulations e.g. those which are sufficiently viscous or which become so on contact with the mucosal surfaces of the esophagus
  • Suitable formulations include those described in WO 2009/109569, the contents of which are herein incorporated by reference.
  • Topical administration involving direct contact of the composition with the intended site or sites in the epithelial surface of the esophagus may be achieved by techniques known in the art, e.g. by the use of catheters (e.g. balloon catheters), stents or other appropriate drug delivery systems.
  • catheters e.g. balloon catheters
  • stents e.g. stents or other appropriate drug delivery systems.
  • a stent which can be used to topically administer the composition is described later in this application.
  • Endoscopic methods may, for example, be employed.
  • the viscosity of the composition will be sufficiently low to permit its application.
  • the composition when using a catheter, the composition will usually be in the form of a solution.
  • Suitable formulations for topical application include gels, sprays, powders, films, aerosols, solutions and any other conventional pharmaceutical forms in the art.
  • a product which is in the form of a solution and which may be used in the invention is Hexvix ® .
  • this product comprises 5-ALA hexyl ester.
  • Hexvix ® is an aqueous solution of 5-ALA hexyl ester which is freshly prepared on site from a lyophilized powder of the 5-ALA hexyl ester and a dissolution medium. Hexvix ® may be instilled or, more preferably, sprayed onto the esophagus.
  • Gel formulations may be used in the invention.
  • the 5-ALA ester may contain the 5-ALA ester formulated with, for example, an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • suitable thickening or gelling agents should be non-toxic, non-irritant and devoid of leachable impurities. They should be inert towards the active ingredients, i.e. should not promote its degradation.
  • Powders for use in the invention may be formed with the aid of any suitable powder base.
  • Sprays and solutions may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing, solubilising or suspending agents. Aerosol sprays are conveniently delivered from pressurised packs with the use of a suitable propellant.
  • compositions may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, flavouring agents, odour enhancers and/or adsorption enhancers, e.g. surface penetrating agents as mentioned below, and the like.
  • Solubilizing and/or stabilizing agents may also be used, e.g. cyclodextrins (CD) ⁇ , ⁇ , ⁇ and HP-cyclodextrin.
  • the 5-ALA ester is released from the composition on contact with the mucosa-lined surface of the esophagus.
  • the compositions may be formulated so as to provide rapid release of the 5-ALA ester after administration to the subject by employing procedures well known in the art.
  • Preferred are compositions formulated for release of the 5-ALA ester within a period of from 15 minutes to 1 hour, preferably 20 to 45 minutes, following administration. It is desirable that the compositions should maintain contact with the esophageal surface for a sufficient period to permit the uptake of the 5-ALA esters.
  • a gelling agent is used to maintain contact with the esophageal surface for a sufficient period to permit the uptake of the 5-ALA esters.
  • thermosetting gels examples include hydrogels and in-situ gelling agents such as thermosetting gels (or thermoreversible gels).
  • thermosetting gels or thermoreversible gels.
  • One embodiment of a thermosetting gel is one which is liquid at ambient temperature (e.g. 25°C) and more viscous at body temperature (e.g. 37°C).
  • hydrogels examples include polyacrylic hydrogels, cellulose polymers (e.g. carboxymethylcellulose (CMC) polymer), and the like.
  • CMC carboxymethylcellulose
  • Controlled release includes rapid release as well as prolonged or sustained release, although generally it will be desirable that this should be delivered rapidly on contact with the mucosal surface.
  • One way in which controlled release may be achieved is by appropriate selection of a bioadhesive, for example by selecting a bioadhesive which is capable of providing delayed (sustained) release of the active component of the formulation.
  • Bioadhesive systems suitable for use in this regard are generally known and described in the art and include, in particular, the polymeric bioadhesives herein described. Such systems can be adjusted to control the release rate of active by varying the amount of cross-linking agent in the polymer.
  • a suitable embodiment of a polymer for use in this regard is Polycarbophil which is commercially available from B. F. Goodrich under the tradename Noveon ® -AA1. Polycarbophil is a polyacrylic acid cross-linked with divinyl glycol.
  • compositions for use in the invention may also be provided in a form adapted for oral or parenteral administration, for example by intravenous injection.
  • Alternative pharmaceutical forms thus include plain or coated tablets, capsules, suspensions and solutions containing the 5-ALA ester optionally together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol,
  • inert conventional carriers and/or diluents e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol,
  • composition for use according to the invention optionally comprises one or more
  • dosage forms for oral administration are those which are capable of releasing the 5-ALA ester as it travels down the patient's esophagus, i.e. on contact with the mucosal surface.
  • dosage forms include high viscosity solutions or suspensions (e.g. syrups), lozenges, pastilles, etc.
  • Lozenges are a suitable form for administration. On sucking, these slowly dissolve in the patient's mouth thereby releasing the 5-ALA ester down the esophagus.
  • lozenges which include components capable of slowing the passage of the active down the esophagus, thereby maximising the period of contact with the mucosal tissues, are provided.
  • these may contain a carrier, e.g. a polyhydric alcohol carrier or corn syrup and will, in general, also contain one or more thickening, lubricating and/or wetting agents.
  • Spraying of the compositions onto the surface of the esophagus at the desired site may also be used to administer the 5-ALA ester, either in the form of solid fine particles or in the form of tiny droplets of a solvent containing the dissolved 5-ALA ester.
  • an aerosol may deliver a fine powder comprising a 5-ALA ester which dissolves on contact with the moist mucosal surface.
  • concentration of the 5-ALA ester in the compositions for use in the invention depends upon the nature of the 5-ALA ester, the mode of administration and the subject to which it is administered and may be varied or adjusted according to choice. Generally, however, concentration ranges of 0.01 to 50% by weight, such as 0.05 to 20% by weight, or 1 to 10% by weight, e.g. 1 to 5% by weight.
  • compositions herein described include thickening agents. Such agents swell as they absorb liquid and thus may be used to improve the viscosity and consistency of the pharmaceutical product. Gums like gellan gum, xanthan gum, guar gum and carrageenan; or cellulose derivatives like carboxymethylcellulose and
  • (meth)acrylates may be used as thickening agents.
  • suitable thickening agents are polyacrylic acids (carbomer) or wax or waxy solids e.g. solid fatty alcohols or solid fatty acids.
  • Other polymer materials which gel on contact with the fluids of the mucosa-lined surface of the esophagus may also be used.
  • chitin, chitosan and chitosan derivatives such as chitosan salts (hydrochloride, lactate, aspartate, glutamate) and N-acetylated chitosan or N-alkylated chitosan, pectin, alginates (e.g.
  • compositions may further comprise one or more bioadhesive agents, e.g. mucoadhesive agents.
  • Bioadhesives are a class of molecules which are known to form an interaction with materials of a biological nature for an extended period of time by interfacial forces resulting in fixation to a specific biological location.
  • Mucoadhesive agents are a special class of bioadhesive agents which bind to mucous, particularly the glycoprotein mucin which is present in the mucous layer which lines the gastrointestinal tract primarily for protection and lubrication.
  • the attachment of the mucoadhesive to mucin is sufficiently strong so that removal occurs primarily through mucin turnover, i.e. the weaker bond is the mucin-mucin rather than the mucin-mucoadhesive bond.
  • some agents which exhibit an affinity for mucous surfaces bind to the epithelial cells which lie beneath the mucous layer, e.g. lectins, by virtue of specific receptor-mediated interactions.
  • mucoadhesive agent denotes a compound which exhibits an affinity for a mucosa surface, i.e. which adheres to that surface through the formation of bonds which are generally non-covalent in nature, whether binding occurs through interaction with the mucous and/or the underlying cells.
  • the mucosa surface is that of the esophagus.
  • the bioadhesive may itself comprise the carrier or excipient and thus in those cases a further carrier or excipient is optionally present.
  • Suitable mucoadhesive agents may be natural or synthetic compounds, polyanionic, polycationic or neutral, water-soluble or water-insoluble, but are preferably large, e.g. having a molecular weight of 500 kDa to 3000 kDa, e.g. 1000 kDa to 2000 kDa, water insoluble cross-linked, e.g. containing 0.05% to 2% cross- linker by weight of the total polymer, prior to any hydration, water-swellable polymers capable of forming hydrogen bonds.
  • mucoadhesive compounds have a mucoadhesive force greater than 100, especially preferably greater than 120, particularly greater than 150, expressed as a percent relative to a standard in vitro, as assessed according to the method of Smart et al., 1984, J. Pharm. Pharmacol., 36, pp 295-299.
  • Suitable mucoadhesives are described for instance in WO 02/09690, the contents of which are incorporated herein by reference.
  • mucoadhesives for use in the compositions herein described include, polyacrylic hydrogels, chitosan, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, scleroglucan, xanthan gum, pectin, orabase and polygalactonic acid.
  • mucoadhesives may be prepared using standard processes and procedures well-known in the art, although many are available commercially, e.g. from Goodrich, BDH, Hercules, Dow Chemical Co.
  • Mucoadhesive derivatives or salts may also be used. Appropriate salts are as described above in connection with the 5-ALA esters.
  • Mucoadhesive derivatives include chemically modified agents which retain mucoadhesive properties. Such derivatives include those which have been modified to include the 5-ALA ester, such as ALA-methyl ester alginate or esters such as between ALA and
  • hydroxypropyl cellulose may be formed.
  • the 5-ALA ester and the mucoadhesive may be combined into a composition or a product by any appropriate means.
  • the composition may be formulated as a dry polymeric film, tablet or powder.
  • adhesion is likely to occur via hydration, as in the case of cellulose derivatives.
  • Other formulations may be applied in a semi or fully hydrated state (e.g. hydrogels, such as poly (acrylic acid) polymers, hyaluronic acid and chitosan), e.g. by use of an aqueous solution.
  • the mucoadhesive agent may conveniently be provided in a concentration range of 0.05 to 30%, e.g. about 1 to 25 % by weight of the total weight of the pharmaceutical product.
  • the 5-ALA esters may be formulated and/or administered with other active components which serve to enhance the photodynamic effect, for example surface penetration assisting agents and/or chelating agents.
  • the 5-ALA ester may be co-administered with such other optional agents, for example in a single composition or, alternatively, they may be administered separately (e.g. sequentially).
  • a surface penetration assisting agent is used in a pre-treatment step, this may be used at higher concentrations, e.g. up to 100% by weight. If such a pre-treatment step is used, the active component may subsequently be administered up to several hours following pre-treatment, e.g. at an interval of 5 to 60 minutes following pre- treatment.
  • Products and kits which comprise a composition as herein described and, optionally, a surface penetration assisting agent and/or a chelating agent, as a combined preparation for simultaneous, separate or sequential use in a method of photodynamic diagnosis of an abnormality of the epithelial lining of the esophagus form further aspects of the invention.
  • this aspect of the invention provides a kit for use in a method of photodynamic diagnosis of an abnormality of the epithelial lining of the esophagus as herein described, said kit comprising:
  • compositions may, for example, further comprise one or more surface penetration enhancing agents.
  • Such agents may have a beneficial effect in enhancing the photosensitizing effect of the 5-ALA ester present in the
  • Preferred surface penetration enhancing agents are chelators (e.g. EDTA), surfactants (e.g. sodium dodecyl sulfate), non-surfactants, bile salts (sodium deoxycholate), fatty alcohols e.g. oleylalcohol, fatty acids e.g. oleic acid and esters of fatty acids and alcohol, e.g. isopropylmyristate.
  • chelators e.g. EDTA
  • surfactants e.g. sodium dodecyl sulfate
  • non-surfactants e.g. sodium dodecyl sulfate
  • bile salts sodium deoxycholate
  • fatty alcohols e.g. oleylalcohol
  • fatty acids e.g. oleic acid and esters of fatty acids and alcohol, e.g. isopropylmyristate.
  • Examples of appropriate surface penetrating assisting agents include isopropanol, HPE-101 (available from Hisamitsu), DMSO and other dialkylsulphoxides, in particular n- decylmethyl-sulphoxide (NDMS), dimethylsulphacetamide, dimethylformamide (DMFA), dimethylacetamide, glycols, various pyrrolidone derivatives (Woodford et a/., J. Toxicol. Cut. & Ocular Toxicology, 1986, 5: 167-177), and Azone ® (Stoughton et al., Drug Dev. Ind. Pharm. 1983, 9: 725-744), or mixtures thereof.
  • DMSO is, however, preferred due to its anti-inflammatory activities and its stimulatory effect on the activity of the enzymes ALA-synthase and ALA-dehydrogenase (the enzymes which, respectively, form and condense ALA to porphobilinogen) thereby enhancing the formation of the active form, Pp IX.
  • the surface penetration enhancing agent may conveniently be provided in a concentration range of 0.2 to 20% by weight of the total weight of the composition, e.g. about 1 to 15% or 0.5 to 10% by weight of the total weight of the composition.
  • the composition may further comprise one or more chelating agents.
  • Such agents may also have a beneficial effect in enhancing the photosensitizing effect of the 5-ALA ester present in the composition.
  • Chelating agents may, for example, be included in order to enhance the accumulation of PplX since the chelation of iron by the chelating agent promotes its incorporation into PplX to form haem by the action of the enzyme ferrochelatase, thereby leading to a build up of PplX. The photosensitizing effect is therefore enhanced.
  • Suitable chelating agents are aminopolycarboxylic acids and any of the chelants described in the literature for metal detoxification or for the chelation of
  • EDTA EDTA
  • CDTA cyclohexane triamine tetraacetic acid
  • DTPA DTPA
  • DOTA well known derivatives and analogues thereof.
  • EDTA and DTPA are particularly preferred.
  • Other suitable chelating agents are desferrioxamine and siderophores and they may be used alone or in conjunction with aminopolycarboxylic acid chelating agents such as EDTA. Some of these chelating agents do also exhibit surface penetration assisting agent properties, e.g. EDTA.
  • the chelating agent may conveniently be used at a concentration of 0.01 to 12%, e.g. 0.1 to 5% by weight based on the total weight of the composition.
  • the compositions for use in the invention may further comprise one or more pharmaceutically acceptable excipients which are different from the aforementioned excipients.
  • excipients are for instance surfactants, emulsifiers, such as non- ionic or cationic emulsifiers, fillers, binders, spreading agents, solubilizing and/or stabilizing agents (e.g. cyclodextrins (CD) ⁇ , ⁇ , ⁇ and ⁇ - ⁇ cyclodextrin), lubricating agents, flavours (e.g.
  • the desired area for examination is exposed to light to achieve the desired photoactivation and photodynamic diagnosis.
  • the length of time period between administration and exposure to light will depend on the nature of the 5-ALA ester, the nature of the composition and its mode of administration. Generally, it is necessary that the 5-ALA ester within said composition is sufficiently released to be taken up by the cells of the tissue to be diagnosed, converted into a photosensitizer and achieves an effective tissue concentration at the site of diagnosis prior to photoactivation.
  • the incubation time will be up to 10 hours, for example about 10 minutes to 10 hours, e.g. 30 minutes to 7 hours, or 1 hour to 5 hours. Direct local administration will result in shorter waiting times between administration and activation, for example, 10 minutes to 3 hours, e.g. 15 minutes to about 2 hours or 30 minutes to 1 hour. Where systemic uptake is required following oral
  • the waiting time will be longer, for example between 1 and 6 hours, e.g. 2 to 5 hours or 3 to 4 hours. Optimum waiting times to maximise the concentration of the photosensitizer at the target site may readily be determined.
  • the irradiation will generally be applied for a short time with a high light intensity, i.e. a high fluence rate or for a longer time with a low light intensity, i.e. low fluence rate.
  • the wavelength of the light used for irradiation may be selected to achieve the desired photodynamic effect.
  • Blue light having a wavelength typically ranging from 360 to 450 nm will generally be used, giving rise to fluorescence which is measured in the red region (e.g. 550 to 750 nm).
  • irradiation e.g. by lamps or lasers
  • the irradiation will in general be applied at a dose level of 10 to 100 Joules/cm 2 with an intensity of 20-200 mW/cm 2 when a laser is used, or a dose of 10-100 J/cm 2 with an intensity of 50-150 mW/cm 2 when a lamp is applied.
  • a fibre optic carrying a laser light may be fed through an endoscope to accomplish exposure to irradiation. Exposure may be adjusted, as required, by varying the time of exposure and/or the light intensity.
  • Fluorescence from the excited photosensitizer may be detected using any conventional fluorescence detector.
  • the emitted fluorescence (e.g. at about 635 nm) is used to selectively detect abnormal cells or tissues, e.g. affected cancerous tissue or pre-cancerous tissue (e.g. dysplasia) or non-cancerous conditions (e.g. metaplasia).
  • the fluorescence detected may be used to produce an image of the desired area or areas of the esophagus. Different levels of fluorescence intensity may then be used to identify the different types of cells which may be present. Those areas in which pre-cancerous (e.g.
  • dysplastic or cancerous cells are present give rise to a higher fluorescence intensity, i.e. a positive fluorescence contrast, compared to normal squamous epithelial tissue.
  • Those areas in which metaplastic cells are present give rise to a lower fluorescence intensity, i.e. a negative fluorescence contrast, compared to normal cells.
  • positive and negative contrast in a fluorescence intensity image may be used to map the different areas of the esophagus.
  • the invention thus provides a method of in vivo imaging of a portion of the epithelial lining of the esophagus, said method comprising the following steps:
  • differences in fluorescence intensity from different tissue types present at the target site may be detected, these differences in fluorescence intensity being indicative of the presence or absence of an abnormality.
  • the method of imaging may be performed on a subject pre-administered with said 5-ALA ester or pharmaceutically acceptable salt thereof.
  • detection of a low fluorescence intensity is indicative of the presence of a metaplastic tissue or a normal tissue, whereby the fluorescence of the metaplastic tissue is lower compared to the fluorescence of the normal tissue.
  • detection of a high fluorescence intensity is indicative of a dysplastic, neoplastic or cancerous tissue, whereby the fluorescence of the dysplastic and neoplastic tissue is lower compared to the fluorescence of the cancerous tissue.
  • Suitable endoscopes are known in the art and may be adapted to allow emission of blue light (for excitation purposes) in addition to white light, e.g. by being equipped with an internal filter assembly which passes primarily blue light.
  • a foot pedal may be used to allow convenient switching between white and blue light.
  • the light source may be a laser or a lamp.
  • the endoscope may be equipped with an integrated filter which blocks most of the reflected blue light.
  • a camera such as a modified color charge-coupled device (CCD) camera, may be used to capture images of the esophagus and a standard color monitor may be used to display images of the esophagus. Irradiation is preferably performed for 2 to 60 minutes, e.g. from 5 to 30 minutes.
  • CCD modified color charge-coupled device
  • a single irradiation may be used or alternatively a light split dose in which the light dose is delivered in a number of fractions, e.g. a few minutes to a few hours between irradiations, may be used. Multiple irradiations may also be applied.
  • the area of examination may further be inspected by use of white light, e.g. before, during or after irradiation with blue light. Cancerous tissue or pre-cancerous tissue identified due to its fluorescence may be removed during irradiation or in white light.
  • this may then be treated through alternative therapeutic techniques, e.g. by surgical or chemical treatment.
  • alternative therapeutic techniques e.g. by surgical or chemical treatment.
  • current treatments include surgical treatment, endoscopic ablation therapy, chemical ablation (e.g. by PDT), thermal ablation or mechanical ablation.
  • further application of the 5-ALA ester compound at the site of interest may be carried out in order to effect PDT. It will be appreciated that PDT may require higher
  • concentrations of 5-ALA esters for destruction of the abnormal cells or tissues than used in the diagnostic methods.
  • concentration ranges of up to 50% by weight preferably 10 to 50% by weight, e.g. 15 to 30% by weight, are suitable.
  • Methods and modes of administration have been considered before with regard to the diagnostic uses and are applicable also to therapeutic methods.
  • diagnostic techniques herein described will primarily be carried out in vivo, these may also be carried out in vitro in order to examine cells or tissues which have been removed from the esophagus by biopsy.
  • the invention thus provides a method of in vitro diagnosis of an abnormality of the epithelial lining of the esophagus by assaying a sample of body tissue from the esophageal lining, said method comprising at least the following steps:
  • the present invention relates to esophageal stents for use in the methods of photodynamic diagnosis disclosed herein, more specifically an esophageal stent which is coated with a 5-ALA ester or a pharmaceutically acceptable salt thereof.
  • Stents for use in delivering therapeutic agents, including photosensitive agents, to a body lumen have been described previously, however these have been developed for very different applications to the present invention. Primarily, these are described for use in treating conditions within the vascular system where the stent serves to maintain the desired shape of the vessel, e.g. by opening or maintaining a passageway for the flow of blood. In such cases, the therapeutic agent is chosen for its ability to prevent or reduce any constrictive intraluminal disease such as restenosis.
  • WO 2007/030478 describes a stent coated with an energy-activatable agent for long-term implantation into vessels to prevent obstruction of the vessel (e.g. by breaking down atherosclerotic plaques in arteries), the release of the active agent being controlled by a light stimulus which may be delivered to the patient after an extended time period.
  • WO 94/15583 describes a slow-release drug-eluting stent for treatment of atherosclerosis, in particular restenosis of blood vessels following treatment of atherosclerotic plaques, by destroying the proliferating smooth muscle cells lining the vessel using a photosensitive agent and so preventing further obstruction.
  • the purpose of this device is to maintain patency of vessels both by its physical presence in the vessel and by delivering active agents to breakdown proliferating cardiovascular tissue and thereby prevent flow obstruction.
  • Such a device is not suitable for use in the esophagus, and does not address the problem of providing an alternative method for the controlled delivery of photosensitive agents for use in the diagnosis and treatment of esophageal abnormalities such as Barrett's esophagus.
  • the esophageal stent for use in the method of the invention comprises a generally cylindrical stent body having a surface coating comprising a 5-ALA ester or a pharmaceutically acceptable salt thereof (also referred to herein as the "active agent").
  • Stents including those suitable for use in the esophagus, are generally known and used in the art and may take a variety of forms. Any known type of stent which is suitable for deployment in the esophagus may be employed in the invention.
  • the underlying structure (i.e. framework) of the stent body is not particularly limiting provided that this is capable of delivery to the esophagus and can be held in place (e.g. following radial expansion) to allow for contact with the surface tissue of the esophagus and delivery of the active agent.
  • the stent may be of the self-expandable type or the balloon-expandable type and will typically comprise an open framework onto which the active agent can be applied.
  • the framework will generally be such that the stent can be delivered in a collapsed state (e.g. crimped onto a catheter) to enable this to pass safely down the esophagus before being expanded at the deployment site. Once in position, the stent can then be expanded, e.g. by inflation of a dilation balloon.
  • the stent body can be made of any material which is acceptable for introduction into the body. For example, this may be made of any bio-compatible material having the necessary physical characteristics for the chosen design of stent.
  • Suitable stent materials are those which will not irritate the esophageal wall following deployment or cause any adverse reaction and include metals and polymers.
  • suitable metals include stainless steel, tantalum, cobalt alloys (e.g. cobalt-chromium alloys), platinum alloys (e.g. platinum-iridium alloys), and nickel alloys (e.g. nickel-titanium alloys).
  • Polymeric stents may be made from biostable or biodegradable polymer materials. Those made from biostable materials will generally be removed once the active agent has been delivered to the esophageal wall or, dependent on their light transmission characteristics, after PDD has been carried out.
  • Biodegradable polymers are those which degrade or dissolve in the body. These have the advantage that they may not need to be removed from the esophagus following deployment, especially if these are transparent to light and so may be left in place during the PDD procedure. Depending on the nature of the polymer material, in some cases these may degrade before photoactivation is carried out.
  • Suitable biodegradable polymeric materials may be selected from the group consisting of poly-lactic acids, poly-glycolic acids, collagen, polycaprolactone, hyaluronic acid, polydioxanone, polycaprolactone, polygluconate, poly-lactic acid- polyethylene oxide copolymers, poly(hydroxybutyrate), polyanhydrides, polyphosphoesters, poly(amino acids), and poly(alpha-hydroxy acids).
  • the nature of the biodegradable polymer may be chosen depending on the desired absorption rate.
  • Biostable polymers may also be used to form the stent body. Such materials include silicones, poly(ethylene terephthalate) and polyacetals.
  • Polymer-coated metals may also be used to form the stent body. These may comprise any combination of the polymer materials and metals hereinbefore described.
  • the stent body will typically comprise a framework or mesh made from a plurality of filaments or 'struts' which may be interwoven or inter-linked. Often the filaments will form a zig-zag or sinusoidal wave structure which enables the stent to be radially expanded from a contracted state.
  • the stent coating which carries the active agent will generally cover the entire stent surface, i.e. both the inner and outer surfaces. However, in some cases, the stent coating will only be applied to the outer (i.e. tissue-contacting) surface.
  • the coating may consist of a single coating or multiple coatings. Where multiple coatings are present, one or more of the individual layers may contain the active agent, preferably all layers. In some cases, it may, however, be desirable to apply an outer protective layer which need not necessarily contain any active agent.
  • the size of the stent may readily be selected according to need and will depend on factors such as the age and size of the patient to be treated, the extent of the abnormality to be treated or diagnosed, etc.
  • the stent diameter should be such that, in use (i.e. in the expanded state), its outer surface contacts the esophagus wall such that the active agent can be delivered by contact transfer.
  • the length of the stent may be chosen according to the extent of the area or areas within the esophagus to be treated. For example, a longer stent extending up to 25 or 30 cm may be used in a method of treatment or diagnosis to be performed on the entire length of the esophagus. Shorter stents may be used to treat a more localised area or areas.
  • the thickness of the stent coating will be dependent on factors such as the desired concentration of the active agent, the nature and amount of any other excipients which may be present in the coating, the presence of multiple coating layers (e.g. whether there is any base coat and/or top coat present), etc. Suitable thicknesses can readily be determined by those skilled in the art. Typically, these will be of the order of several micrometres, e.g. from about 3 to about 20 micrometres, or from about 5 to about 10 micrometres.
  • the thickness of the stent body and coating should be selected accordingly. Suitable thicknesses may readily be selected such that the stent degrades entirely in vivo over a time period ranging from 2 to 24 hours.
  • Suitable coating materials and methods for application of these to the stent body, in particular to its tissue-contacting surface, are generally known in the art, e.g. in
  • WO 2012/004399 to Photocure ASA should be capable of securing an effective amount of the desired active agent onto the body of the stent (the active should be present in a therapeutically or diagnostically effective amount); and able to keep this in place during delivery and expansion of the stent in vivo.
  • the coating may be selected such that this controls the rate of delivery of the active agent from the stent to the esophageal wall.
  • Methods suitable for use in preparing the coated stents herein described may comprise the following steps:
  • the coating may be provided in the form of a powder, i.e. a dry, bulk solid composed of a large number of very fine particles, more preferably in the form of a compressed powder, i.e. having lost its ability to flow.
  • the dry pharmaceutical composition is in the form of a cake, i.e. a dry bulk solid formed into a small block.
  • the coating is in the form of a film, i.e. one or more (thin) layers of dry/dried material, preferably a relatively homogeneous film which covers substantially the whole surface of the stent or substantially the outer surface of the stent. In a further preferred embodiment, this film is well attached and stays well attached to the stent surface, i.e. is relatively stable under mechanical stress which may occur during transport and shipment and during deployment in vivo.
  • the coating may be obtained as a film by film coating processes known in the art, preferably by dip-coating or spray-coating. Such methods are discussed in detail in WO 2012/004399, the contents of which are incorporated herein by reference. ln a preferred embodiment, one or more polymers and optionally other
  • Preferred one or more polymers are polymers which have good film- forming properties and/or good gel forming properties. Preferred other
  • pharmaceutically acceptable excipients are selected from one or more of the following compounds: plasticizers, coloring agents and thickening agents.
  • Other pharmaceutically acceptable excipients which may be present in the coating are disintegrants, mucoadhesive agents, surface penetration enhancing agents and chelating agents.
  • the active agent may be present in the range of 0.25 to 50%, for example 0.5 to 30%, such as 0.5 to 15% or 1 to 10% or 1 to 7% by weight of the total weight of the coating.
  • the active agent may be present in the range of 50 to 99%, for example 60 to 91 % or 75 to 90% by weight of the total weight of the coating.
  • the active agent may be present in the range of 15 to 85%, for example 20 to 80% such as 25 to 78% or 26 to 60% by weight of the total weight of the coating.
  • All one or more polymers and pharmaceutically acceptable excipients should be non-toxic, non-irritant and devoid of leachable impurities. They should be inert towards the active agent, i.e. should not promote its degradation.
  • One or more of each pharmaceutically acceptable excipient compound may be used, e.g. one or more plasticizers, one or more coloring agents, etc.
  • the one or more polymers for use in the coatings can be natural, semi-natural, i.e. derivatives of natural polymers which are obtained by a chemical reaction, or synthetic polymers; they may be homopolymers or copolymers.
  • polymers are used which have good film-forming properties, i.e. which form - together with the active agent - a film when deposited on the stent surface.
  • a preferred group of such polymers are starch, cellulose and derivatives of starch and cellulose.
  • Preferred starch derivatives are starch acetate and carboxymethyl starches, preferably with an amylose content of at least 18% by weight.
  • One preferred cellulose is microcrystalline cellulose.
  • Other preferred cellulose derivatives are cellulose ethers such as methylcellulose, ethylcellulose,
  • hydroxyethylcellulose hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethyl-cellulose and carboxymethylcellulose.
  • Such polymers may be used in combination with other polymers, e.g. ethylcellulose with
  • hydroxypropylmethylcellulose Other preferred cellulose derivatives are cellulose acetate phthalate and nitrocellulose. Further preferred polymers are rosin and rosin esters.
  • Another preferred group of polymers are (meth) acrylate polymers and copolymers. The use of "meth" as a prefix in parenthesis indicates, in accordance with common practice, that the polymer molecule is derived from monomers having the carbon atom skeleton of either or both of acrylic acid and methacrylic acid. Such polymers and copolymers are e.g. based on methylmethacrylate,
  • ethylacrylate, methacrylic acid and trimethylammonioethylmethacrylate chloride e.g. anionic and cationic polymers of methacrylic acid, copolymers of
  • methacrylates copolymers of acrylates and methacrylates, copolymers of ethylacrylates and methylmethacrylates.
  • Other preferred polymers are polyvinyl acetate phthalate.
  • cellulose and cellulose derivatives, especially cellulose ethers, are used as one or more polymers in the coatings herein described.
  • polymers with good gel-forming properties may be used, i.e. which form - together with the active agent - gels on contact with water and fluids of mucosa lined surfaces.
  • Preferred such polymers are gums, preferably gellan gum, xanthan gum and carrageenan.
  • Other preferred polymers are chitin, chitosan and chitosan derivatives such as chitosan salts (hydrochloride, lactate, aspartate, glutamate) and N-acetylated chitosan or N-alkylated chitosan.
  • Yet other preferred polymers are pectin, alginates, e.g. sodium alginate, pullulan, hyaluronic acid and derivatives thereof.
  • polymers with good film-forming properties and good gel-forming properties are used, e.g. cellulose ethers like methylcellulose, ethylcellulose, gellan gum, chitosan and chitosan derivatives, pullulan, alginates, hyaluronic acid, derivatives of hyaluronic acid or carrageenan.
  • cellulose ethers like methylcellulose, ethylcellulose, gellan gum, chitosan and chitosan derivatives, pullulan, alginates, hyaluronic acid, derivatives of hyaluronic acid or carrageenan.
  • Preferred such polymers are cellulose ethers like methylcellulose, ethylcellulose,
  • Polymers with good film-forming properties are preferably used if the coating should form a film.
  • the polymers may be water soluble or insoluble in water. In a preferred embodiment
  • water soluble polymers are used.
  • the one or more polymers may conveniently be provided in a concentration range of 50 to 99.75%, for example 70 to 99.5%, e.g. 85 to 99.5%, or 90 to 99% or 93 to 99% by weight of the total weight of the coating.
  • the one or more polymers may be present in the range of 1 to 50 %, for example 9 to 40% or 10 to 25% by weight of the total weight of the coating.
  • the one or more polymers may be present in the range of 20 to 65%, for example 25 to 62% such as 30 to 55% or 40 to 54% by weight of the total weight of the coating.
  • plasticizers are also pharmaceutically acceptable excipients which may be present in the coating.
  • plasticizers In general their use is to reduce the glass transition temperature of a polymer making it more elastic and deformable, i.e. flexible. Hence they may be present in the coating if one or more polymers are present, preferably if one or more film-forming polymers are present.
  • Plasticizers are preferably chosen in such a way that they work well with the given polymer(s). In one embodiment, suitable plasticizers are acting as a good solvent for the polymer(s) in question. In another embodiment, if water soluble polymers are used, the plasticizer is preferably a water miscible compound.
  • Suitable plasticizers are low molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate, citrate esters such as triethyl, tributyl and acetyl citrate, dibutyl sebacate, camphor, triacetin, oils and glycerides such as castor oil, acetylated
  • glycol monoglycerides and fractionated coconut oil.
  • Glycerol and propylene glycol are also common plasticizers, they should however not be used if the coating contains as an active ingredient lower alkyl ALA esters or salts thereof, such as CrC 8 -alkyl ALA esters since they may promote degradation of such active ingredients.
  • the plasticizers may conveniently be provided in a concentration range of 1 to 30%, for example 5 to 20% or 7 to 15% by weight of the total polymer weight.
  • the plasticizers may be provided in a higher concentration range, for instance in a concentration range of 10 to 175%, or 35 to 150% or 37 to 80% by weight of the total polymer weight.
  • coloring agents such as synthetic dyes or pigments, e.g. titanium dioxide or yellow iron oxide. Pigments usually decrease the permeability of the coating to water vapor and oxygen and may thus increase its shelf life. Further, they contribute to the total solids of the liquid used to obtain the coating without significantly contributing to its viscosity. Thus faster processing time by virtue of more rapid drying is possible, which is particularly significant for aqueous based liquids used in spray-coating.
  • the coloring agents may conveniently be provided in a concentration range of 0.1 to 20%, for example 0.5 to 10% or 1 to 5% by weight of the coating.
  • thickening agents are used in liquids which are employed in dip-coating.
  • the choice of thickening agents is dependent on whether the liquid is an aqueous or aqueous based liquid or whether non-aqueous solvents are used to form the liquid.
  • Some of the afore-mentioned polymers have thickening properties, e.g. gums like guar gum, cellulose derivatives like carboxymethylcellulose and (meth)acrylates.
  • thickening agents are polyacrylic acids (carbomer) or wax or a waxy solids e.g. solid fatty alcohols or solid fatty acids. If present in the coating, the thickening agents may conveniently be provided in such an amount that the desired viscosity of the liquid described above is obtained. The actual amount will depend on the one or more solvent said liquid comprises and the nature of the thickening agent.
  • disintegrants aid in the break up of the coating when it is put into a moist environment.
  • Some of the aforementioned polymers do exhibit disintegrant properties, e.g. certain celluloses, starch and derivatives thereof. If these polymers are present, there may not be a need or desire to add any further disintegrants.
  • More effective disintegrants are referred to as superdisintegrants. Those include for instance alginic acid, croscarmellose, crospovidone and sodium starch glycolate. Such compounds swell when they come in contact with fluids but they do not form a gel which would decrease their disintegration properties.
  • the disintegrants may conveniently be provided in a concentration range of 0.1 to 10% by weight of the total weight of the coating, for example 0.25 to 5% or 0.5 to 4% by weight.
  • the coatings may further comprise one or more mucoadhesive agents.
  • mucoadhesive agent denotes a compound which exhibits an affinity for a mucosa surface, i.e. which adheres to that surface through the formation of bonds which are generally non-covalent in nature, whether binding occurs through interaction with the mucous and/or the underlying cells.
  • Suitable mucoadhesive agents may be natural or synthetic compounds
  • polyanionic, polycationic or neutral, water-soluble or water-insoluble but are preferably large, e.g. having a molecular weight of 500 kDa to 3000 kDa, e.g. 1000 kDa to 2000 kDa, water-insoluble cross-linked, e.g. containing 0.05% to 2% cross- linker by weight of the total polymer, prior to any hydration, water-swellable polymers capable of forming hydrogen bonds.
  • mucoadhesive compounds have a mucoadhesive force greater than 100, especially preferably greater than 120, particularly greater than 150, expressed as a percent relative to a standard in vitro, as assessed according to the method of Smart et al., 1984, J. Pharm. Pharmacol., 36, pp 295-299.
  • Some of the afore-mentioned polymers exhibit mucoadhesive properties, for instance gums like guar gum, chitosan and chitosan derivatives, pullulan, sodium alginate or hyaluronic acid. If these polymers are present, there may not be a need or desire to add any further mucoadhesive agents.
  • Suitable mucoadhesive agents are selected from polysaccharides, preferably dextran, pectin, amylopectin or agar; gums, preferably guar gum or locust bean gum; salts of alginic acid, e.g. magnesium alginate; poly(acrylic acid) and crosslinked or non-crosslinked copolymers of poly(acrylic acid) and derivatives of poly(acrylic acid) such as salts and esters like for instance carbomer (carbopol).
  • the mucoadhesive agent may conveniently be provided in a concentration range of 0.05 to 30%, e.g. about 1 to 25 % by weight of the total weight of the coating.
  • the coating may further comprise one or more surface penetration enhancing agents. Such agents may have a beneficial effect in enhancing the coating
  • photosensitizing effect of the active agent e.g. of 5-ALA, the derivative of 5-ALA or the precursor of 5-ALA present in the coating.
  • Preferred surface penetration enhancing agents are chelators (e.g. EDTA), surfactants (e.g. sodium dodecyl sulfate), non-surfactants, bile salts (sodium deoxycholate), fatty alcohols e.g.
  • the surface penetration enhancing agent may conveniently be provided in a concentration range of 0.2 to 20% by weight of the total weight of the coating, e.g. about 1 to 15% or 0.5 to 10% by weight of the total weight of the coating.
  • the coating may further comprise one or more chelating agents.
  • Such agents may also have a beneficial effect in enhancing the photosensitizing effect of the active agent.
  • Their ability to enhance the photosensitizing effect of the active agent means that a lower amount of the active agent needs to be taken up by the cells in order to achieve the desired photodynamic effect. This has the advantage that less time is generally needed for the cells to take up an effective amount of the photosensitizing agent or precursor thereof.
  • Chelating agents may, for example, be included in order to enhance the
  • Suitable chelating agents are aminopolycarboxylic acids and any of the chelants described in the literature for metal detoxification or for the chelation of paramagnetic metal ions in magnetic resonance imaging contrast agents. Particular mention may be made of EDTA, CDTA (cyclohexane triamine tetraacetic acid), DTPA and DOTA and well known derivatives and analogues thereof. EDTA and DTPA are particularly preferred.
  • chelating agents are desferrioxamine and siderophores and they may be used alone or in conjunction with aminopolycarboxylic acid chelating agents such as EDTA. Some of these chelating agents do also exhibit surface penetration assisting agent properties, e.g. EDTA.
  • Preferred chelators are iron-chelators such as CP 94 (1 ,2-diethyl-3-hydroxypyridin-4-one) as described in Bech et al., Journal of Photochemistry and Photobiology B: Biology 41 (1997), 136-144, or Deferasirox such as described in US-A-6,596,750. Where present, the chelating agent may conveniently be used at a concentration of 0.01 to 12%, e.g. 0.1 to 5% by weight based on the total weight of the coating.
  • the coating may further comprise one or more pharmaceutically acceptable excipients which are different from the afore-mentioned excipients.
  • excipients are for instance surfactants, emulsifiers, preferably non-ionic or cationic emulsifiers, fillers, binders, spreading agents, stabilizing agents or preservatives.
  • suitable excipients based on their purpose.
  • Common excipients that may be used in the pharmaceutical products herein described are listed in various handbooks (e.g. D.E. Bugay and W.P. Findlay (Eds)
  • the stent according to the invention can be used to deliver the active agent to the esophageal wall by introducing the stent down the esophagus and, if necessary, radially expanding this into contact with the desired portion of the esophageal wall.
  • Esophageal delivery may be achieved using known techniques such as by a catheter or using other stent expanding devices. Radial expansion may be achieved by balloon expansion of the stent (e.g. where a balloon catheter is used) or by self-expansion. When the stent is balloon-expandable, this will generally be formed in the expanded state, crimped onto a balloon dilation catheter or other stent expanding device for delivery.
  • the stent is expanded into place, e.g. by the radial expansion of the balloon.
  • the active agent is released from the stent coating in a moist environment, i.e. upon contact with the mucosa-lined surface of the esophagus.
  • excipients need to be chosen in such a way that they are either dissolved upon contact with the mucosa-lined surfaces of the esophagus or at least disintegrate to allow release of the active ingredient.
  • the excipients, especially any polymers present, thus need to be dissolved or disintegrated at the given pH on said mucosa-lined surface.
  • the invention thus provides the use of an esophageal stent in any of the methods herein described, wherein the stent has a coating capable of releasing a 5-ALA ester or a pharmaceutically acceptable salt thereof, e.g. 5-ALA hexyl ester.
  • the release profile (immediate/quick, sustained and delayed release) and the residence time of the coating at the target area of the esophagus in which treatment or diagnosis is to be performed, can be influenced by the choice of the polymer as well.
  • a quick release of the active agent may be preferred if a comparably high concentration of the active agent at the site of treatment is desired.
  • a delayed release of the active ingredient may be preferred if a low concentration of the active agent at the site of treatment is desired.
  • an immediate release of the active is generally preferred.
  • the stent may be removed prior to carrying out PDD. Depending on the nature of the stent body, however, this may not be necessary and indeed, in some cases, it can be desirable to leave the stent in situ whilst carrying out photoactivation since this has the benefit of holding open the esophagus such that the light dose necessary to activate the
  • photosensitizer can readily reach the esophageal surface.
  • Polymeric stents may be transparent to light or at least sufficiently transparent that they permit an effective light dose to reach the target site and to permit the resulting fluorescence to be observed. Such "transparent" stents therefore need not be removed before PDD. After PDD has been carried out these may either be removed or, in the case where these are biodegradable, may be left at the site.
  • Metallic stents are not transparent to light and so will typically be removed before carrying out photoactivation.
  • the invention thus provides a method of photodynamic diagnosis of an abnormality of the epithelial lining of the esophagus, said method comprising the following steps:
  • Another aspect of the invention is a 5-ALA ester, or a pharmaceutically acceptable salt thereof, for use in a method of photodynamic diagnosis of an abnormality of the epithelial lining of the esophagus, said method comprising the following steps:
  • Figure 1 is a graph showing normalized fluorescence of PplX in the esophagus following administration of 5-ALA and 5-ALA hexyl ester;
  • Figure 2 is a graph showing the intensity of PplX fluorescence in the Barrett's (metaplastic) and normal mucosa following administration of 5-ALA hexyl ester.
  • Example 1 Comparative study of the fluorescence induced by 5-ALA and 5-ALA hexyl ester in the mucosae of the human esophagus presenting a Barrett type of mucosae
  • LIFS Spectrofluorimetry
  • LIFS was carried out using the Karl Storz D-light system. Abnormal cells could be clearly delineated against normal tissue due to the porphyrin fluorescence resulting from an accumulation of the ALA or HAL in the abnormal tissue.
  • blue light of a specific spectral composition was introduced into the body via an endoscopic light guide system.
  • Patient group 1 5 subjects each received 20 mg/kg body weight ALA orally,
  • Patient group 2 3 subjects each received a 8 mM solution of HAL in an
  • aqueous buffer by local instillation 100 mg in 50 mL, i.e. 0.2%), 2 hours before endoscopy.
  • Normalised fluorescence intensity of PplX in the esophagus is shown in Figure 1 for both patient groups.
  • the large standard deviation that can be seen in this figure is due to the interpatient fluctuation of the fluorescence intensity.
  • the intensity of fluorescence induced by HAL presents a profile between the normal epithelium and the Barrett epithelium (metaplastic epithelium) similar to ALA, i.e. porphyrin fluorescence was significantly higher in normal tissue compared to Barrett's tissue for both patient groups.
  • the intensity of fluorescence is lower with HAL in the normal epithelium.
  • Figure 2 shows the fluorescence intensity of PplX in the Barrett and normal mucosa in one of the patients receiving HAL. A stronger intensity for the normal mucosa is observed.
  • HAL also provides a more reliable diagnostic procedure than ALA when used to distinguish between normal and Barrett's epithelium

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Abstract

Cette invention concerne le diagnostique d'anomalies de la surface tapissée par un épithélium de l'œsophage et, en particulier, l'utilisation d'esters d'acide 5-aminolévulinique (5-ala) dans des méthodes de diagnostic (PDD) de l'œsophage de Barrett et dans des méthodes de diagnostic qui surveillent la progression de la maladie avec une spécificité élevée.
PCT/EP2012/070346 2011-10-14 2012-10-12 Diagnostic photodynamique d'anomalies du tissu épithélial sous-jacent de l'œsophage au moyen d'un ester de 5-ala WO2013053927A1 (fr)

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US14/351,770 US20140276107A1 (en) 2011-10-14 2012-10-12 Photodynamic diagnosis
EP12770170.4A EP2766049A1 (fr) 2011-10-14 2012-10-12 Diagnostic photodynamique d'anomalies du tissu épithélial sous-jacent de l' sophage au moyen d'un ester de 5-ala

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015583A1 (fr) 1993-01-08 1994-07-21 Pdt Systems, Inc. Extenseurs a liberation de medicaments
WO1996028412A1 (fr) 1995-03-10 1996-09-19 Photocure As Esters de l'acide 5-aminolevulinique en tant qu'agents photosensibilisants en photochimiotherapie
WO2002009690A2 (fr) 2000-07-27 2002-02-07 Photocure Asa Composition
WO2002010120A1 (fr) 2000-07-27 2002-02-07 Photocure Asa Esters de l'acide 5-aminolevulinique utilises comme agents photosensibilisateurs en photochimiotherapie
WO2003011265A2 (fr) 2001-07-26 2003-02-13 Photocure Asa Methode
WO2003041673A2 (fr) 2001-11-16 2003-05-22 Ecole Polytechnique Federale De Lausanne (Epfl) Procede d'epilation des poils
US6596750B2 (en) 1996-06-25 2003-07-22 Novartis Ag Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
WO2005092838A1 (fr) 2004-03-26 2005-10-06 Photocure Asa Sels d'addition acide d'acide 5-aminolevulinique ou de ses derives
WO2006051269A1 (fr) 2004-11-10 2006-05-18 Photocure Asa Traitement de l’acne a l’aide de derives de l’acide 5-aminolevulinique
WO2007030478A2 (fr) 2005-09-06 2007-03-15 Light Sciences Oncology, Inc. Dispositif implantable pour traitement therapeutique a l'interieur d'une lumiere corporelle
WO2009109569A2 (fr) 2008-03-06 2009-09-11 Ge Healthcare As Agents esters pour imagerie
WO2012004399A1 (fr) 2010-07-09 2012-01-12 Photocure Asa Compositions sèches et dispositifs les contenant destinés à être utilisés dans la thérapie photodynamique ou le diagnostic photodynamique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0814960D0 (en) * 2008-08-15 2008-09-24 Ge Healthcare As Method for detecting dysplasia

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015583A1 (fr) 1993-01-08 1994-07-21 Pdt Systems, Inc. Extenseurs a liberation de medicaments
WO1996028412A1 (fr) 1995-03-10 1996-09-19 Photocure As Esters de l'acide 5-aminolevulinique en tant qu'agents photosensibilisants en photochimiotherapie
US6034267A (en) 1995-03-10 2000-03-07 Photocure As Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
US6596750B2 (en) 1996-06-25 2003-07-22 Novartis Ag Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
WO2002009690A2 (fr) 2000-07-27 2002-02-07 Photocure Asa Composition
WO2002010120A1 (fr) 2000-07-27 2002-02-07 Photocure Asa Esters de l'acide 5-aminolevulinique utilises comme agents photosensibilisateurs en photochimiotherapie
WO2003011265A2 (fr) 2001-07-26 2003-02-13 Photocure Asa Methode
WO2003041673A2 (fr) 2001-11-16 2003-05-22 Ecole Polytechnique Federale De Lausanne (Epfl) Procede d'epilation des poils
WO2005092838A1 (fr) 2004-03-26 2005-10-06 Photocure Asa Sels d'addition acide d'acide 5-aminolevulinique ou de ses derives
WO2006051269A1 (fr) 2004-11-10 2006-05-18 Photocure Asa Traitement de l’acne a l’aide de derives de l’acide 5-aminolevulinique
WO2007030478A2 (fr) 2005-09-06 2007-03-15 Light Sciences Oncology, Inc. Dispositif implantable pour traitement therapeutique a l'interieur d'une lumiere corporelle
WO2009109569A2 (fr) 2008-03-06 2009-09-11 Ge Healthcare As Agents esters pour imagerie
WO2012004399A1 (fr) 2010-07-09 2012-01-12 Photocure Asa Compositions sèches et dispositifs les contenant destinés à être utilisés dans la thérapie photodynamique ou le diagnostic photodynamique

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas", 2002, EDITION CANTOR
"Handbook of Pharmaceutical Salts", 2002, PUBLISHER HELVETICA CHIMICA ACTA
"Lexikon der Hiifsstoffefur Pharmazie, Kosmetik und angrenzende Gebiete", 1989, EDITION CANTOR
"Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", 1989, EDITION CANTOR AULENDORF
"Pharmaceutical excipients", 1999, MARCEL DEKKER
BARTELSMAN ET AL., EUR. J. CANCER PREVENTION, vol. 1, 1992, pages 323 - 325
BECH ET AL., JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B: BIOLOGY, vol. 41, 1997, pages 136 - 144
BRAND ET AL., GASTROINTESTINAL ENDOSCOPY, vol. 56, no. 4, 2002, pages 479 - 487
COLLAUD ET AL., JOURNAL OF CONTROLLED RELEASE, vol. 23, 2007, pages 203 - 210
COLLAUD ET AL: "Clinical evaluation of bioadhesive hydrogels for topical delivery of hexylaminolevulinate to Barrett's esophagus", JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 123, no. 3, 30 October 2007 (2007-10-30), pages 203 - 210, XP022321355, ISSN: 0168-3659, DOI: 10.1016/J.JCONREL.2007.08.015 *
ENDLICHER E ET AL: "Endoscopic fluorescence detection of low and high grade dysplasia in Barrett s oesophagus using systemic or local 5-aminolaevulinic acid sensitisation", GUT, BRITISH MEDICAL ASSOCIATION, LONDON, UK, vol. 48, 1 January 2001 (2001-01-01), pages 314 - 319, XP007910445, ISSN: 0017-5749, DOI: 10.1136/GUT.48.3.314 *
ENDLICHER ET AL., GUT, vol. 48, 2001, pages 314 - 319
KRIEG R C UIHLEIN D ET AL: "Improving the use of 5-aminolevulinic acid (ala)-induced protoporphyrin IX (prix) for the gastrointestinal tract by esterification - An in vitro study", CELLULAR AND MOLECULAR BIOLOGY, CMB ASSOCIATIONS, NOISY-LE-GRAND, FR, vol. 48, no. 8, 1 January 2002 (2002-01-01), pages 917 - 923, XP008114594, ISSN: 0145-5680 *
N. FOTINOS ET AL., PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 82, 2006, pages 994 - 1015
SMART ET AL., J. PHARM. PHARMACOL., vol. 36, 1984, pages 295 - 299
STEPHAN BRAND ET AL: "Detection of high-grade dysplasia in Barrett s esophagus by spectroscopy measurement of 5-aminolevulinic acidinduced protoporphyrin IX fluorescence", GASTROINTESTINAL ENDOSCOPY, ELSEVIER, NL, vol. 56, no. 4, 1 January 2002 (2002-01-01), pages 479 - 487, XP007910444, ISSN: 0016-5107, DOI: 10.1067/MGE.2002.128172 *
STEPINAC ET AL., ENDOSCOPY, vol. 35, no. 8, 2003, pages 663 - 668
STEPINAC T ET AL: "Endoscopic Fluorescence Detection of Intraepithelial Neoplasia in Barret's Esophagus after Oral Administration of Aminolevulinic acid", ENDOSCOPY, GEORG THIEME VERLAG, DE, vol. 35, no. 8, 1 August 2003 (2003-08-01), pages 663 - 668, XP008114553, ISSN: 0013-726X *
STOUGHTON ET AL., DRUG DEV. IND. PHARM., vol. 9, 1983, pages 725 - 744
WOODFORD ET AL., J. TOXICOL. CUT. & OCULAR TOXICOLOGY, vol. 5, 1986, pages 167 - 177

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